Structure-bioactivity relationship study on anticancer Pd and Pt complexes with aliphatic glycine derivative ligands.

To investigate the structure and bioactivity relationship, six Pd(II)/Pt(II) complexes with N-isobutylglycine (L1) and cyclohexylglycine (L2) as N^O amino acid bidentate ligands, 1,10'-phenanthroline (phen) and 2,2'-bipyridine (bipy) as N^N donor ligands, and [Pd(L1)(bipy)]NO3 (1), [Pd(L2)(bipy)]NO3 (2), [Pd(L1)(phen)]NO3 (3), [Pd(L2)(phen)]NO3·2H2O (4), [Pt(L1)(phen)]NO3 (5), along with [Pt(L2)(phen)]NO3 (6) were prepared and then characterized. The geometry of each compound was validated by doing a DFT calculation. Furthermore, tests were conducted on the complexes' water solubilities and lipophilicity. All bipy complexes had superior aqueous solubility and less lipophilicity in comparison with phen complexes, as well as complexes containing cyclohexyl-glycine compared to isobutyl-glycine complexes, probably because of the steric effects and polarity of cyclohexylglycine. The in-vitro anticancer activities of these compounds were examined against HCT116, A549, and MCF7 cancerous cell lines. Data revealed that all Pd/Pt complexes demonstrate higher anticancer activity than carboplatin, and complexes 3 and 4 are more cytotoxic than cisplatin against the HCT116 cell line, particularly against MCF7 cancerous cells. In addition, among all compounds, complex 4 has more anticancer ability than oxaliplatin. Due to different solubility and lipophilicity behavior, the accumulation of Pt complexes and clinical Pt drugs in each cancerous cell was investigated. The binding capabilities of these complexes to DNA, as the main target in chemotherapy, occur through minor grooves and intercalate into DNA, which was done using absorption, fluorescence, and circular dichroism spectroscopy. Finally, the docking simulation study showed the mode of DNA bindings is in good agreement with the spectral binding data.

Biological Activity of Two Anticancer Pt Complexes with a Cyclohexylglycine Ligand against a Colon Cancer Cell Line: Theoretical and Experimental Study.

Because of their extraordinary ability to disrupt the natural structure of nucleic acids, metal complexes could be used in cancer therapy. In this study, cyclohexylglycine (HL) as a ligand and two new Pt complexes, [Pt(NH3)2(L)]NO3 (1) and [Pt(bipy)(L)]NO3 (2), were synthesized and characterized by elemental analysis, LC-MS, UV-vis spectrometry, FT-IR, 1H NMR spectroscopy, 13C NMR spectroscopy, 195Pt NMR spectroscopy, HPLC analysis, and single-crystal X-ray diffraction. Complex 2 crystallized in the orthorhombic Pbca space group, and density functional theory (DFT) was used to describe its structural parameters were described in detail. These complexes can be classified as oral medications and drug-like molecules based on a comparison of their absorption, distribution, metabolism, and excretion assessment. Quantum chemical descriptors (QCDs) were determined using DFT calculations to predict the tendency of DNA to approach these complexes. During the determination of the function of the metallodrug in DNA binding, the fluorescence data indicated that static quenching took place for all ligands and complexes with higher DNA binding affinity. CD and isothermal absorption studies indicate the presence of electrostatic and groove binding for the amine derivative and that DNA binds with the bipy moiety via groove binding. Furthermore, the interaction modes were determined using molecular docking to investigate the binding of these compounds with the target DNA molecule. According to docking investigations, binding energies of -5.7, -11.56, and -10.00 kcal/mol for HL and complexes 1 and 2, respectively, indicate partially electrostatic and groove binding. The anticancer activities of the Pt(II) complexes were tested against the HCT116 human colon cancer cell line, with IC50 values of 35.51 and 51.33 µM for 1 and 2, respectively, after 72 h. These values show that the inhibitory effect of complex 1 was better than those of 2 and carboplatin (IC50 = 51.94 µM).

Property evaluation of two anticancer candidate platinum complexes with N-isobutyl glycine ligand against human colon cancer.

Small molecules have potential usage in cancer therapy due to their remarkable potency of disarranging the natural structure of nucleic acids. In this study, two complexes [Pt(NH3)2(IBgly)]NO3 (1) and [Pt(bipy)(IBgly)]NO3 (2) based on Pt(II), N-isobutylglycine (IBgly), 2,2'-bipyridine, and ammonia were prepared and characterized by spectroscopic methods. Pharmacokinetic ADME data, absorption, distribution, metabolism, excretion, and bioavailability radar showed two complexes can be introduced for Pt-based anti-cancer drugs. Mechanism of tumor inhibition and DNA interaction of these compounds was studied by UV-Vis, fluorescence, and CD spectroscopies. Also, thermodynamic parameters and the binding constants were calculated through absorption measurements. The fluorescence data showed that a static quenching mechanism occurred for both complexes with a binding constant and binding affinity towards DNA (Kb ≈ 3500 M-1 and kq ≈ 2.1 × 1011 M-1 s-1). The thermodynamic parameters indicated electrostatic approaching and groove binding were more feasible than intercalation mode between Pt(II) complexes and DNA. CD spectra indicated the increasing intensity of the positive band and the negative band decreasing. Density functional theory calculations confirmed the experimental data and determined the quantum chemical descriptors including total energy, hardness, chemical potential, electrophilicity, electronegativity, etc. According to this, the binding tendency of these compounds with DNA could be predicted. Further, molecular docking studies were also performed. Docking studies revealed that the desolvation, hydrogen, and electrostatic binding were effective for the interaction between complexes and DNA with binding energy (- 10.44 and - 9.57 kcal/mol) for complexes 1 and 2, respectively, which is mainly of partially electrostatic and groove binding type. The cytotoxic activity of Pt complexes was examined against human colon cancer cell line which indicated good activity with IC50 values of (41.66 and 47.30 µM) for both complexes after 72 h, respectively. Also, they demonstrated more inhibitory effects compared to carboplatin.

Effects of N-oxidation on the molecular and crystal structures and properties of isocinchomeronic acid, its metal complexes and their supramolecular architectures: experimental, CSD survey, solution and theoretical approaches.

Nine coordination complexes and polymer (M/L/X) based on Co, Ni, Zn, Cu (M), pyridine-N-oxide-2,5-dicarboxylic acid (H2pydco) (L) and either isonicotinamide (Ina), piperazine (pipz), 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) (X) were synthesized and characterized by elemental analyses, infrared spectroscopy and single crystal X-ray diffraction. The resulting empirical formulae of the prepared complexes are [Co(H2O)6][Co(pydco)2(H2O)2]·2H2O (1), [M(pydco)(H2O)4]2 [M = Co (2), Ni (3), Zn (4)], [Co(pydco)(bipy)(H2O)2]·4H2O (5), [Co(pydco)(phen)(H2O)2]·5.135(H2O)·0.18(EtOH) (6), [Cu(Hpydco)(bipy)Cl]·2H2O (7), [Cu(Hpydco)(bipy)Cl]2·2H2O (8), and {[AgCu(H2O)2(phen)(pydco)]NO3} n (9). With the exception of 9, which forms an extended structure via multiple coordination modes, all the complexes contain (H)pydco as a bidentate ligand coordinated to the metal ion via the N-oxide and the adjacent carboxylate group oxygen atom, creating a chelate ring. The metal centers exhibit either distorted octahedral (1-6) or square pyramidal (7-9) geometry. Our results demonstrate that, when acting cooperatively, non-covalent interactions such as X-H⋯O hydrogen bonds (X = O, N, C), C-O⋯π and π⋯π stacking represent driving forces for the selection of different three-dimensional structures. Moreover, in compounds 2-4, 1D supramolecular chains are formed where O⋯π-hole interactions are established, which unexpectedly involve the non-coordinated carboxylate group. The non-covalent interaction (NCI) plot index analysis reveals the existence of the O⋯π-hole interactions that have been evaluated using DFT calculations. The Cremer and Pople ring puckering parameters are also investigated. The complexation reactions of these molecules with M were investigated by solution studies. The stoichiometry of the most abundant species in the solution was very close to the corresponding crystals. Finally, the effect of N-oxidation on the geometry of complexes has been also studied using the Cambridge Structural Database. It shows that complexes containing N-oxidized H2pydc are very rare.